Anders Paerregaard

ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents

Background: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. Methods: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. Results: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. Conclusions: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Management of Pediatric Ulcerative Colitis: Joint ECCO and ESPGHAN Evidence-based Consensus Guidelines

Background and Aims: Pediatric ulcerative colitis (UC) shares many features with adult-onset disease but there are some unique considerations; therefore, therapeutic approaches have to be adapted to these particular needs. We aimed to formulate guidelines for managing UC in children based on a systematic review (SR) of the literature and a robust consensus process. The present article is a product of a joint effort of the European Crohns and Colitis Organization (ECCO) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). Methods: A group of 27 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to ESPGHAN and ECCO members. A list of 23 predefined questions were addressed by working subgroups based on a SR of the literature. Results: A total of 40 formal recommendations and 68 practice points were endorsed with a consensus rate of at least 89% regarding initial evaluation, how to monitor disease activity, the role of endoscopic evaluation, medical and surgical therapy, timing and choice of each medication, the role of combined therapy, and when to stop medications. A management flowchart, based on the Pediatric Ulcerative Colitis Activity Index (PUCAI), is presented. Conclusions: These guidelines provide clinically useful points to guide the management of UC in children. Taken together, the recommendations offer a standardized protocol that allows effective, timely management and monitoring of the disease course, while acknowledging that each patient is unique.

Effect of probiotic Lactobacillus strains in young children hospitalized with acute diarrhea.

Background. Oral bacteriotherapy promotes recovery from acute childhood diarrhea, but few strains have been shown to have therapeutic potentials. We examined the effect of two newly identified probiotic Lactobacillus strains in acute childhood diarrhea. Methods. Sixty-nine children were randomized during hospitalization for acute diarrhea to receive a mixture of Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246, 1010 colony-forming units of each strain or placebo twice daily for 5 days. Before selection of these stains their potential probiotic characteristics were demonstrated in vitro and in healthy volunteers. Results. In patients receiving probiotics, the diarrheal phase was reduced by 20%. The duration of diarrhea was 82 h in the treatment group vs. 101 h in the control group (not significant, P = 0.07). However, 3 of 30 patients from the treatment group vs. 13 of 39 from the control group still had loose stools at the end of the study period (P = 0.03). In patients with diarrhea for <60 h before start of treatment (early intervention), a clear effect of the probiotics was demonstrated (80 h in the treatment group vs. 130 h in the control group, P = 0.003). After early intervention, the length of hospitalization was reduced by 48% (3.5 vs. 1.7 days, P = 0.03). At the end of the intervention, rotavirus antigen was found in 12% of patients from the treatment group vs. 46% from the control group (P = 0.02). Conclusions. The two probiotics, L. rhamnosus 19070-2 and L. reuteri DSM 12246, ameliorated acute diarrhea in hospitalized children and reduced the period of rotavirus excretion. Oral bacteriotherapy was associated with a reduced length of hospital stay. The beneficial effects were most prominent in children treated early in the diarrheal phase.

Effect of probiotic Lactobacillus strains on acute diarrhea in a cohort of nonhospitalized children attending day-care centers

Background. Certain strains of lactobacilli have been shown to promote recovery from rotavirus enteritis in hospitalized children. Few studies have examined the effect of probiotics in nonhospitalized children with mild diarrhea. Methods. We studied in a randomized placebo-controlled trial the effect of lyophilized Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246, 1010 colony-forming units of each strain twice daily for 5 days, on acute diarrhea in children in a cohort of children recruited from local day-care centers. The duration of diarrhea and assessment of stool consistency were recorded by the parents. Results. In patients treated with the selected Lactobacillus strains, the mean duration of diarrhea after intervention was reduced (76 h in patients treated with probiotics vs. 116 h in the placebo group;P = 0.05). In patients with diarrhea for <60 h before start of treatment (early intervention), a more pronounced effect of probiotics was found. The time to recovery after early treatment was 79 h vs. 139 h in the placebo group (P = 0.02); 1 of 17 patients treated early vs. 6 of 13 in the control group still had loose stools 120 h after start of treatment (P = 0.03). Conclusions. In children from day-care centers with mild gastroenteritis, the combination of L. rhamnosus 19070-2 and L. reuteri DSM 12246 was effective in reducing the duration of diarrhea.

Case Study of the Distribution of Mucosa-Associated Bifidobacterium Species, Lactobacillus Species, and Other Lactic Acid Bacteria in the Human Colon

ABSTRACT The distribution of mucosa-associated bacteria, bifidobacteria and lactobacilli and closely related lactic acid bacteria, in biopsy samples from the ascending, transverse, and descending parts of the colon from four individuals was investigated by denaturing gradient gel electrophoresis (DGGE). Bifidobacterial genus-specific, Lactobacillus group-specific, and universal bacterial primers were used in a nested PCR approach to amplify a fragment of the 16S rRNA gene. DGGE profiles of the bifidobacterial community were relatively simple, with one or two amplicons detected at most sampling sites in the colon. DGGE profiles obtained with Lactobacillus group-specific primers were complex and varied with host and sampling site in the colon. The overall bacterial community varied with host but not sampling site.

Pediatric inflammatory bowel disease: increasing incidence, decreasing surgery rate, and compromised nutritional status: A prospective population-based cohort study 2007-2009.

Background: The aim was to evaluate the incidence, treatment, surgery rate, and anthropometry at diagnosis of children with inflammatory bowel disease (IBD). Methods: Patients diagnosed between January 1, 2007 to December 31, 2009 in Eastern Denmark, Funen, and Aarhus were included from a background population of 668,056 children <15 years of age. For evaluation of incidence, treatment, and surgery rate, a subcohort from Eastern Denmark was extracted for comparison with a previously published population‐based cohort from the same geographical area (1998–2006). Results: In all, 130 children with IBD: 65 with Crohns disease (CD), 62 with ulcerative colitis (UC), and three with IBD unclassified (IBDU) were included. The mean incidence rates per 106 in 2007–2009 were: IBD: 6.4 (95% confidence interval [CI]: 5.4–7.7), CD: 3.2 (2.5–4.1), UC: 3.1 (2.4–4.0) and IBDU: 0.2 (0.05–0.5). Comparing the two cohorts from Eastern Denmark we found higher incidence rates for IBD (5.0 and 7.2 in 1998–2000 and 2007–2009, respectively, P = 0.02) and CD (2.3 versus 3.3, P = 0.04). Furthermore, we found a significant decrease in surgery rates (15.8/100 person‐years versus 4.2, P = 0.02) and an increase in the rate of initiating immunomodulators (IM) within the first year (29.0/100 person‐years versus 69.2, P < 0.001). IM use was associated with a trend towards a decreased surgery risk (relative risk [RR] 0.38; 0.15–1.0). Children with CD had poor nutritional status at diagnosis compared with the general pediatric population. Conclusions: Over the past 12 years we found an increase in the incidence of IBD in children, an increasing use of IM, and decreasing 1‐year surgery rates. CD patients had poor nutritional status.

Disease phenotype at diagnosis in pediatric Crohn's disease: 5-year analyses of the EUROKIDS Registry.

Background:It has been speculated that pediatric Crohns disease (CD) is a distinct disease entity, with probably different disease subtypes. We therefore aimed to accurately phenotype newly diagnosed pediatric CD by using the pediatric modification of the Montreal classification, the Paris classification. Methods:Information was collected from the EUROKIDS registry, a prospective, web-based registry of new-onset pediatric IBD patients in 17 European countries and Israel. When a complete diagnostic workup was performed (ileocolonoscopy, upper gastrointestinal [GI] endoscopy, small bowel imaging), CD patients were evaluated for ileocolonic disease extent, esophagogastroduodenal involvement, and jejunal/proximal ileal involvement. Disease behavior and the occurrence of granulomas were also analyzed. Results:In all, 582 pediatric CD patients could be classified according to the Paris classification. Isolated terminal ileal disease (±limited cecal disease) was seen at presentation in 16%, isolated colonic disease in 27%, ileocolonic disease in 53%, and isolated upper GI disease in 4% of patients. In total, 30% had esophagogastroduodenal involvement and 24% jejunal/proximal ileal disease. Patients with L2 disease were less likely to have esophagogastroduodenal involvement or stricturing disease than patients with L1 or L3 disease. Terminal ileal disease and stricturing disease behavior were more common in children diagnosed after 10 years of age than in younger patients. Granulomas were identified in 43% of patients. Conclusions:Accurate phenotyping is essential in pediatric CD, as this affects the management of individual patients. Disease phenotypes differ according to age at disease onset. The Paris classification is a useful tool to capture the variety of phenotypic characteristics of pediatric CD.

Infliximab dependency in a national cohort of children with Crohn's disease.

Aim: The aim was to evaluate the pattern of responsiveness and to monitor side effects of episodic administration of infliximab in children with active Crohns disease (CD) treated in Denmark from 1999 to 2003. Material and Methods: The National Danish Crohn Colitis Database of infliximab was used to identify all Danish CD patients treated at pediatric departments with infliximab. The clinical outcome was assessed by pattern recognition of the disease course 30 days after the first infliximab infusion and 90 days after intended end of treatment. Results: During a 3 year period, infliximab was given to 24 CD patients (9 male/15 female) aged median 15.4 (range 9.8-18.6) years with a median disease duration of 26 (range 0.7-93) months and a median number of infusions of 6 (range 2-11). Five milligrams of infliximab per kilogram infusions were given intravenously. Immediate response was as follows: 8 (33%) patients achieved complete response (CR), 10 (42%) partial response (PR), and 6 (25%) no response (NR). Long-term response was as follows: 7 (29%) patients achieved prolonged response (PRO), defined as maintenance of CR or PR, 10 (42%) were infliximab dependent (ID), defined as relapse of symptoms requiring reinfusions of infliximab to regain CR or PR, and 6 (25%) had NR. Six (25%) patients needed surgery during or after treatment with infliximab. Side effects were seen in four (17%) patients. No serious events were noted. Conclusion: Seventy-one percent of the children appeared to benefit (PRO or ID) from infliximab treatment with minor side effects when given episodically. Among these patients, two response patterns were recognized: PRO after ending infliximab treatment (29%) or dependency on reinfusions of infliximab (42%).

Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results of a 5-year audit of the EUROKIDS registry.

Objective: In 2005, the Inflammatory Bowel Disease (IBD) Working Group of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition published consensus guidelines on the diagnostic workup of paediatric IBD, the Porto criteria. According to these guidelines, children suspected of having IBD should undergo an oesophagogastroduodenoscopy (OGD), ileocolonoscopy, and (except in cases of definitive ulcerative colitis) adequate imaging of the small bowel. To audit and evaluate the diagnostic workup of paediatric patients with IBD in Europe, the Working Group created EUROKIDS, a prospective, Web-based registry of newly diagnosed paediatric patients with IBD. Methods: Patients with IBD (ages 0–18 years) were registered in 44 centres in 18 countries. Data on diagnostic workup were analysed according to the year of diagnosis, type of IBD, and centre size. Diagnostic yield of OGD and ileal intubation were evaluated. Results: Between 2004 and 2009, 2087 newly diagnosed patients were correctly registered. Both OGD and ileocolonoscopy had been performed in 64% of all of the patients and increased significantly from year 1 (52 %) to 5 (71%, P < 0.001). Small-bowel follow-through use decreased during the years (year 1 n = 213, year 5 n = 108; P < 0.001), whereas magnetic resonance imaging use increased (year 1 n = 25, year 5 n = 171; P < 0.001). Patients diagnosed as having Crohn disease (CD, 59%) and ulcerative colitis (58%) were more likely to have had a complete diagnostic workup than patients diagnosed as having IBD unclassified (45%). In CD, the diagnostic yield of OGD was 7.5% and the yield of ileal intubation was 13%. Conclusions: The quality of diagnostic workup in paediatric patients with IBD increased steadily between 2004 and 2009. Small-bowel imaging by magnetic resonance imaging superseded the use of small-bowel follow-through. OGD and ileal intubation contributed to a definitive diagnosis of CD.